Overexpression of SphK2 contributes to ATRA resistance in colon cancer through rapid degradation of cytoplasmic RXRα by K48/K63-linked polyubiquitination
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Wen-Na Shi1, Shu-Xiang Cui2, Zhi-Yu Song1, Shu-Qing Wang1, Shi-Yue Sun1, Xin-Feng Yu1, Ye Li1, Yu-Hang Zhang1, Zu-Hua Gao3 and Xian-Jun Qu1
1Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
2Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, China
3Department of Pathology, McGill University, Montreal, Quebec, Canada
Xian-Jun Qu, email: [email protected]
Zu-Hua Gao, email: [email protected]
Keywords: sphingosine kinase 2 (SphK2), retinoid therapy resistance, cytoplasmic RXRα, polyubiquitination
Received: December 06, 2016 Accepted: March 26, 2017 Published: April 18, 2017
The resistance mechanisms that limit the efficacy of retinoid therapy in cancer are poorly understood. Sphingosine kinase 2 (SphK2) is a highly conserved enzyme that is mainly located in the nucleus and endoplasmic reticulum. Unlike well-studied sphingosine kinase 1 (SphK1) located in the cytosol, little has yet understood the functions of SphK2. Here we show that SphK2 overexpression contributes to the resistance of all-trans retinoic acid (ATRA) therapy in colon cancer through rapid degradation of cytoplasmic retinoid X receptor α (RXRα) by lysine 48 (K48)- and lysine 63 (K63)-based polyubiquitination. Human colonic adenocarcinoma HCT-116 cells transfected with SphK2 (HCT-116Sphk2 cells) demonstrate resistance to ATRA therapy as determined by in vitro and in vivo assays. Sphk2 overexpression increases the ATRA-induced nuclear RXRα export to cytoplasm and then rapidly degrades RXRα through the polyubiquitination pathway. We further show that Sphk2 activates the ubiquitin-proteasome system through the signal mechanisms of (1) K48-linked proteosomal degradation and (2) K63-linked ubiquitin-dependent autophagic degradation. These results provide new insights into the biological functions of Sphk2 and the molecular mechanisms that underlie the Sphk2-mediated resistance to retinoid therapy.
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